ABSTRACT The adult mammalian heart shows little or no significant innate regeneration of cardiac muscle after injury, and instead heals by scarring. This regenerative deficiency has major socioeconomic consequences, given that ischemic myocardial infarction is a leading cause of morbidity and mortality in the United States and over 5 million Americans suffer from heart failure. Many years ago, we found that the teleost zebrafish displays a vigorous regenerative response after partial resection of the cardiac ventricle, involving creation of new cardiomyocytes with little or no scarring. This discovery pioneered the model system approach to heart regeneration that is employed by many laboratories today. For the past 15 years, the principal investigator has introduced new tools and strategies to reveal many key concepts and mechanisms underlying heart regeneration in zebrafish. Here, we describe an integrative program that defines at new resolution the molecular components of innate heart regeneration, as well as mechanisms by which these components are regulated. We will harness this information to innovate new methods for controlling the efficacy of heart regeneration across species, including attempts to stimulate regeneration in mammals through factor delivery and gene regulation using viral vectors. The discoveries we make will continue to inform the fundamental biology of heart regeneration, and they will directly relate to ideas and methods to enhance regeneration and reduce the incidence of heart failure in humans. They are also likely to extend beyond cardiovascular biology and have relevance to the repair of other tissues.